Terfenadine is an antagonist of the H-1 histamine receptor protein, which mediates the response antagonized by conventional antihistamines. Terfenadine is well absorbed but is extensively metabolized. See Okerholm et al., Biopharmaceutics and Drug Distribution, 2: 185-190 (1981). Two main metabolites have been identified and one of the metabolites, fexofenadine, chemically named 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl-1-piperidinyl)butyl]-.alpha.,.alp ha.-dimethylbenzeneacetic acid, is reported to have antihistaminic activity. See Gartiez et al., Arzneimittel Forschung/Drug-Research; 32: 1185-1190 (1982).
Recently, the FDA has approved the use of fexofenadine as a prescription antihistamine (ALLEGRA.RTM.) for allergic rhinitis. Fexofenadine is said to have the beneficial effects of terfenadine while having a reduced risk of cardiotoxicity. See, e.g., U.S. Pat. No. 5,375,683.
It has been suggested that the moderate effectiveness of some H.sub.1 -antihistamines are due to their additional activity against leukotrienes, particularly LTD.sub.4. In one study of guinea pigs, the increase in airway resistance caused by LTD.sub.4 (leukotriene D.sub.4) was suppressed by terfenadine. See Akagi et al., Oyo Yakuri, 35: 361-371 (1988). Another study was conducted that investigated the development of dual antagonists of H.sub.1 - and LTD.sub.4 -receptors. Twenty (20) H.sub.1 -antihistamines with diverse chemical structures were tested for activity against LTD.sub.4 -induced contraction in isolated guinea-pig ileum and displacement of [.sup.3 H]LTD.sub.4 from guinea-pig lung membrane proteins [M. Zhang et al., Inflamm. res. 46:Supp. I S93-S94 (1997)]. The results indicated the drugs were weakly active in inhibiting LTD.sub.4 -induced contraction of guinea pig ileum. The study further mentioned a possible mechanism for loratadine and terfenadine, but concluded that the mechanism does not appear to warrant great attention for drug development.
Similarly, F. Baroody et al. report that terfenadine treatment partially inhibits the early nasal response to allergen challenge and subsequent reactivity to a challenge with methacholine without affecting the influx of eosinophils into nasal secretions. Treatment tended to decrease levels of tryptase, prostaglandin D.sub.2 and leukotriene C.sub.4, but the differences did not achieve statistical significance relative to the placebo [F. Baroody et al., Arch. Otolaryngol. Head Neck Surg., 122:309-316 (Mar. 1996)].
Compounds within the class of non-sedating antihistamines have been known to cause severe adverse electrophysiologic side-effects when administered to a human. These adverse side-effects are associated with a prolonged QT interval and include, but are not limited to, ventricular fibrillation and cardiac arrhythmias, such as ventricular tachyarrhythmias or torsades de pointes. Quercia et al., Hosp. Formul. 28: 137, 142 (1993); Knowles, Canadian Journal Hosp. Pharm., 45: 33,37 (1992); Craft, British Medical Journal, 292: 660 (1986); Simons et al., Lancet, 2: 624 (1988); and Unknown, Side Effects of Drugs Annual, 12: 142 and 14: 135. More recently, clinical practitioners have noted an increase in the occurrence of these cardiac arrhythmias upon co-administration of terfenadine with other drugs such as ketoconazole and erythromycin or upon overdose of terfenadine. Quercia et al., Hosp. Formul. 28: 137, 142 (1993).
Leukotrienes augment neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increase capillary permeability, and smooth muscle contraction, all of which contribute to inflammation, edema, mucus secretion, and bronchoconstriction. For example, zileuton, commercially available as ZYFLO.RTM., is a specific inhibitor of 5-lipoxygenase and has the chemical name (.+-.)-1-(1-Benso[b]thien-2-ylethyl)-1-hydroxyurea. Zileuton is known to inhibit leukotriene (LTH.sub.4, LTC.sub.4, LTD.sub.4, and LTE.sub.4) formation in vitro. Zileuton is an inhibitor ex vivo of LTB.sub.4 formation in several species and inhibits leukotriene-dependent smooth muscle contractions in vitro in guinea pig and human airways. One study of 373 patients indicated that 600 mg of zileuton four times daily were required to provide efficacy, while 400 mg failed to do so. In some patients, zileuton was reported to cause headache, pain, asthenia, dyspepsia, nausea, and myalgia. [Physician's Desk Reference, 52 ed., Medical Economics Co., Inc., 474-76 (1998)].
Zafirlukast, sold commercially as ACCOLATE.RTM., is another type of leukotriene inhibitor. This leukotriene inhibitor is a leukotriene receptor antagonist (LTRA) of leukotriene D.sub.4 and E.sub.4, and has the chemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-8-ylmethyl)-3-methoxy-N-o -tolylsulfonylbenzamide. Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma. In vitro studies indicated that zafirlukast antagonized the contractile activity of three leukotrienes in conducting airway smooth muscle from laboratory animals and humans; prevented intradermal LTD.sub.4 -induced increases in cutaneous vascular permeability; and inhibited inhaled LTD.sub.4 -induced influx of eosinophils into animal lungs. In some patients, zafirlukast has been reported to cause headache, infection, nausea, diarrhea, pain, asthenia, abdominal pain, dizziness, myalgia, fever, vomiting, SGPT elevation, and dyspepsia. [Physician's Desk Reference, 52 ed., Medical Economics Co., Inc., 3148-49 (1998)].